Bivalent Norovirus Vaccine Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bivalent Norovirus Vaccine Study (NCT01168401), a randomized phase 1 study. The primary outcome is Number of Participants With Solicited Local Adverse Events (AEs) Post Dose 1.

2. Clinical Question

The study’s stated aims also included assessing serum antibody responses and other immune measures after vaccination. These included antibody-secreting cells, homing markers, and memory B-cell responses directed against norovirus antigens. The registry lists antibody titers, fold rises, and seroresponse measures among secondary outcomes.

The clinical question is therefore broader than a single safety count. It covers both solicited local reactions after the first vaccination and immunogenicity measures across vaccine dose levels and control groups. The registry’s stated hypotheses include a comparison of adverse-event incidence with other intramuscular vaccines and a comparison of immune responses after two doses versus one. Those hypotheses describe questions the trial set out to examine; they should not be read as results.

3. Trial Design

This was a randomized, triple-masked, parallel-group phase 1 study. It was multi-site and used a dose-escalation design. The registry describes four dosage levels of the intramuscular Norovirus GI.1/GII.4 bivalent VLP vaccine, adjuvanted with MPL and aluminum hydroxide, with saline or placebo controls. The vaccine description specifies administration on Days 0 and 28. The registry record reports enrollment of 102 and lists the study status as completed.

The listed groups include Cohort A vaccine doses of 5/5, 15/15, 50/50, and 150/150 mcg, with a placebo group. Cohorts B, C, and D include a 50/50 mcg vaccine group and placebo groups. The record does not explain the rationale for the cohort sequence or the allocation within each cohort. A total across the listed group sizes is not stated.

Randomization is intended to reduce systematic differences between groups at assignment. Masking can reduce the influence of expectations on participant reports and study assessments; the record identifies the study as triple-masked but does not describe which individuals were masked or how masking was maintained. A parallel design assigns participants to a study group rather than describing a crossover between treatments.

The study started on 2010-09-03, and the primary completion date is 2013-01-01. The registry describes two planned doses 28 days apart. It does not report a detailed operational protocol, the allocation ratio, a sample-size justification, or the method used to escalate doses. Those details are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Healthy volunteers were enrolled in 1 of the following treatment groups: Bivalent Norovirus GI.1/GII.4 Vaccine (Cohort A: 5/5 microgram \[mcg\], 15/15 mcg, 50/50 mcg, 150/150 mcg; Cohort B: 50/50 mcg; Cohort C: 50/50 mcg and Cohort D: 50/50 mcg) adjuvanted with 50 mcg monophosphoryl lipid A (MPL) and 500 mcg aluminum hydroxide \[Al(OH)3\]) or Placebo.

Only the first 6 of 11 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: mITT population included all participants who received at least 1 dose of study product. Only those categories have been reported below where at least 1 participant experienced the event.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Modified Intent to Treat (mITT) population included all participants who received at least 1 dose of study product.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Solicited Local Adverse Events (AEs) Post Dose 1, measured over Day 0 up to Day 7.

The primary endpoint is the number of participants with solicited local adverse events after Dose 1, during Day 0 up to Day 7. It is a participant-count outcome: the quantity of interest is how many people experienced an event, rather than how many separate episodes occurred. The registry says that solicited events were recorded using a memory aid, and that only categories experienced by at least one participant were reported.

The listed local events are pain, tenderness, swelling, and redness. The registry describes severity categories for these events. Pain and tenderness have event-specific descriptions, while swelling and redness are graded using size and impact on activity. For example, the registry defines severe swelling or redness as greater than 10 cm or as preventing daily activity. The pain and tenderness descriptions also use effects on activity, movement, or rest to distinguish severity.

Soliciting specific symptoms over a defined period can make safety reporting more consistent than relying only on spontaneous reports. This is a general measurement principle: a prespecified question and observation window help clarify what is being counted and when. The endpoint can describe the frequency of reported local reactions after vaccination, but a participant count alone does not convey duration, severity distribution, or the experience of each participant.

The registry record does not present the primary endpoint as one overall vaccine-versus-control comparison. It notes that the endpoint has several categories or time points and is not reduced to a single comparison. A category-level primary result is therefore not reported in the registry record as a single summary estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is a count of participants who experienced an event. Because each participant is classified as having or not having a specified event within the relevant observation window, this kind of outcome is often analyzed as a binary response. General statistical interpretation compares the event proportions between groups, while accounting for the number of participants assessed in each group. The registry record does not report a primary-endpoint estimate or the statistical method used to compare groups.

What does randomization contribute?

Random assignment is designed to make treatment groups comparable on average with respect to both measured and unmeasured characteristics. It does not guarantee that groups will be identical, particularly in a study with small cohorts. Randomization therefore supports a causal comparison in principle, but the quality of the estimate still depends on follow-up, outcome measurement, adherence to the analysis plan, and adequate reporting. The record identifies randomization but does not report the allocation method or allocation ratio.

Why does masking matter for reported symptoms?

Pain, tenderness, swelling, and redness rely in part on participant observation or reporting. Masking can reduce the chance that knowledge of assigned treatment affects reports or assessments. The registry identifies triple masking, but does not specify who was masked, whether any treatment clues could have revealed assignment, or how masking success was assessed. Those details are not reported in the registry record.

How should participant counts be read?

A count should be read alongside its group denominator and the event definition. Counts alone can look different simply because group sizes differ. A proportion can aid comparison, but a calculated proportion should not be substituted for a registry-reported result unless it is explicitly identified as a recalculation. No recalculated primary-endpoint result is reported in the registry record. The listed safety entries give at-risk and affected-participant counts for serious and other adverse events; those summaries are separate from the solicited local-event endpoint.

In general, a confidence interval describes the range of effect estimates reasonably compatible with the data under the method used. It conveys precision as well as the direction and size of an estimated effect. A point estimate without an interval gives less information about uncertainty. The registry record does not report confidence intervals for the primary endpoint. A p-value, if reported, would address compatibility with a specified null model, not the clinical importance of an effect; no primary-endpoint p-value is reported in the record.

What do the planning assumptions mean?

The sample-size material is described as an illustration based on the observed effect. Its assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration considers an effect equal to a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial had a particular probability of detecting an effect. Planning sample sizes are not observed power. The registry record does not report the original sample-size justification or a protocol-based power calculation.

For a binary outcome, a normal approximation can be used in some planning settings to approximate the sampling distribution of a difference in proportions. General statistical guidance is that the approximation may be less dependable when counts are sparse or expected event numbers are small. This study’s groups are cohort-based and include small listed at-risk counts, so any method relying on a large-sample approximation would need to be judged against the actual data and analysis plan. The registry record does not report the inferential method for the endpoint.

Over-dispersion is a general concern when observed variability exceeds what a chosen model assumes. For binary data, clustering or other group-level structure can make observations more alike than a simple independent-participant model allows. That can make standard errors too small if the structure is ignored. The registry describes a multi-site study and multiple cohorts, but does not report whether site or cohort structure was modeled or whether over-dispersion was assessed. It is therefore not possible to say whether such adjustments were used.

What is not inferable from the listed numbers?

Group counts do not by themselves establish a statistically reliable difference. A comparison requires a defined contrast, an analysis population, and a method for handling uncertainty. For a multiple-category endpoint, a single estimate also requires a clear rule about which categories and time points enter the comparison. The record does not supply a single such primary comparison, nor does it report an analysis plan that would explain how to interpret multiple categories. The numerical summaries should therefore be read descriptively rather than as a complete hypothesis test.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 20 outcome measures, including the primary solicited local adverse-event measure and several antibody outcomes. Multiple outcomes and categories create a general multiplicity issue: when many comparisons are considered, the chance of at least one apparently notable result can increase. Prespecified outcome hierarchies or adjustment procedures can help clarify which comparisons are confirmatory and how uncertainty should be interpreted. The registry record does not report a multiplicity strategy, an outcome hierarchy, or an adjustment method.

The primary analysis population is described as the modified intention-to-treat population, including all participants who received at least one dose of study product. The record does not provide a fuller account of exclusions, withdrawals, adherence, or how participants with incomplete assessments were handled. Procedures for missing endpoint data are not reported in the registry record.

The record says that only event categories experienced by at least one participant were reported for the primary endpoint. This reporting rule means that absence of a category from the reported results should not automatically be interpreted as proof that the event was impossible or that all relevant observations were complete. The record does not explain how missing diaries or incomplete symptom assessments were treated.

The registry lists no analyses for the reported outcome set. It does not describe interim analyses, a statistical analysis plan, or methods for adjusting for cohort or site. Those details are not reported in the registry record. Consequently, the available information does not establish whether the listed comparisons were prespecified, exploratory, adjusted, or analyzed with a method that accounts for the study’s multiple outcomes.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: idiopathic central retinal vein occlusion (10.0%), chest pain (10.0%), gastroparesis (10.0%), fractured right fibula (10.0%), bleeding following urologic surgery (10.0%).

The serious adverse-event entries are grouped by cohort and include the number at risk and the number affected. The other-adverse-event entries are reported separately. For example, the record lists one participant affected by a serious adverse event among 10 at risk in the Cohort A1 vaccine group, and two among 10 at risk in the Cohort C vaccine group. These examples are descriptive counts, not estimates of a causal treatment effect. Group sizes and cohort assignments differ, and no comparative statistical analysis is reported in the registry record.

The listed serious adverse-event terms include idiopathic central retinal vein occlusion, chest pain, gastroparesis, fractured right fibula, and bleeding following urologic surgery; each is reported as 10.0%. The denominator underlying those term percentages is not reported in the registry record. Death counts are also not reported in the record.

These serious-event summaries should not be confused with the primary endpoint. The primary endpoint concerns solicited local events after Dose 1 during Day 0 up to Day 7; the serious-event entries are a different safety summary. The registry does not establish from these figures whether an event was caused by vaccination. Sparse counts also provide limited precision, and a zero in a listed group should be read as no affected participant recorded for that entry, not as proof that an event cannot occur.

12. What the Result Does, and Does Not, Mean

The registry record describes a randomized, triple-masked, parallel phase 1 study of a dose-escalation norovirus vaccine in adults. It identifies the primary safety question, the observation window, the modified intention-to-treat population, and selected safety counts across vaccine and placebo cohorts. It also lists a broad set of secondary immunogenicity outcomes.

These details show what the study was designed to assess and what safety information the record reports. They do not, by themselves, establish how the vaccine compares with placebo on the primary endpoint. The primary endpoint is not presented as one consolidated comparison, and a category-level primary result is not reported in the registry record. The study hypotheses about adverse events and immune responses are not findings.

The listed serious and other adverse-event counts are descriptive. They can help readers see the reported counts in individual cohorts, but the record does not supply a complete inferential comparison, confidence intervals, or a causal attribution for the events. The listed serious-event terms and percentages likewise do not establish whether the events were related to study product.

The record also does not provide a full analysis plan, multiplicity approach, missing-data procedures, or original sample-size justification. These omissions limit the ability to evaluate precision, the handling of incomplete observations, and the confirmatory status of multiple outcomes. The planning illustration is not observed power and should not be treated as a result of the trial.

In short, the registry supports a cautious descriptive reading of the design, endpoints, and reported safety entries. It does not support a definitive statement about the comparative safety or immunogenicity of the vaccine, and it should not be read as medical advice.

13. Why This Trial Matters Statistically

This trial illustrates why endpoint definition matters. The primary measure is a participant count for solicited local adverse events after the first dose within a specified window. It is not interchangeable with a general count of all adverse events, serious adverse events, or immune responses. Keeping these outcomes distinct prevents a safety summary from being mistaken for the primary endpoint.

The study also demonstrates the difficulty of interpreting a dose-escalation design with several cohorts and multiple outcome measures. A reader needs to know which groups are compared, which endpoint and time point are primary, and whether the analysis was planned to control multiplicity. The registry identifies the design and outcome families, but does not report a complete analysis plan or one consolidated primary comparison.

Small cohort-level counts require careful attention to uncertainty. A difference in observed counts may reflect a real difference, chance variation, or both. Confidence intervals and clearly described statistical methods would help show how precisely the trial estimates each contrast. Those primary-endpoint details are not reported in the registry record.

Finally, planning illustrations and trial results answer different questions. A planning calculation based on an observed effect and specified assumptions is not evidence of observed power, nor does it replace the original rationale for the trial’s enrollment. The registry record does not report that original justification. These distinctions are useful when reading early-phase studies, where the design may explore safety and immune measures without providing a definitive comparative estimate.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpretation is that the registry record does not provide a single primary-endpoint comparison. The primary outcome includes several event categories or time points, and the record does not reduce these to one estimate. A consolidated contrast, category-specific uncertainty, or a clear inferential analysis is not reported in the registry record.

The study is phase 1 and divided among multiple dose and control cohorts. The listed groups have small at-risk counts, which limits the precision that can ordinarily be expected from group-level event summaries. The record does not provide confidence intervals or a statistical comparison for the primary endpoint, so the precision of any difference cannot be assessed from the available information.

The registry describes a multi-site study, but does not report how site or cohort structure was handled in analysis. It also does not report allocation details, a sample-size justification, multiplicity procedures, missing-data rules, or the statistical analysis plan. The modified intention-to-treat population is defined as participants receiving at least one dose, but further analysis-population details are not reported.

The primary endpoint depends on solicited symptom reporting using a memory aid. This provides a defined way to capture local events, but the record does not describe completeness of the memory aids, handling of incomplete reports, or the distribution of event severity. Only categories with at least one reported participant were included in the primary outcome reporting.

Finally, serious adverse-event counts and terms are descriptive and separate from the primary local-event endpoint. The record does not provide the term-specific denominators, causal assessments, or a complete inferential safety analysis. These limitations constrain conclusions to what is explicitly reported.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Bivalent Norovirus Vaccine Study — NCT01168401.
• Registry record last updated 2018-11-23; status last verified 2018-04.
• Results first posted 2018-11-23.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT01168401 is a completed phase 1 randomized, triple-masked, parallel, multi-site dose-escalation study of an intramuscular Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with MPL and aluminum hydroxide. The registry reports enrollment of 102, a start date of 2010-09-03, and a primary completion date of 2013-01-01.

The primary outcome is the number of participants with solicited local adverse events after Dose 1 during Day 0 up to Day 7. The registry defines the modified intention-to-treat population as participants who received at least one dose. It lists secondary immunogenicity outcomes and cohort-level serious and other adverse-event counts.

The record does not report a single primary-endpoint comparison, confidence intervals, a full statistical analysis plan, multiplicity handling, missing-data procedures, or the original sample-size justification. The available results therefore support descriptive interpretation rather than a definitive comparative conclusion.